Single-cell profiling of BAL in preschool cystic fibrosis reveals macrophage dysregulation and ivacaftor-modified inflammatory programs in the early life lung

Maksimovic, J; Shanthikumar, S; Howitt, G; Dixit, G; Hickey, PF; Anttila, C; Brown, DV; Gubbels, L; Senabouth, A; Amann-Zalcenstein, D; Powell, JE; Ranganathan, SC; Oshlack, A; Neeland, MR

Author(s): Maksimovic, J; Shanthikumar, S; Howitt, G; Dixit, G; Hickey, PF; Anttila, C; Brown, DV; Gubbels, L; Senabouth, A; Amann-Zalcenstein, D; Powell, JE; Ranganathan, SC; Oshlack, A; Neeland, MR;
Details: Publication Year 2026-06,Volume 19,Issue #3,Page 100338
Journal Title: Mucosal Immunology
Publication Type: Research article
Abstract: Aberrant inflammation and structural lung damage occurs early in life for people with cystic fibrosis (CF). Even in the era of CFTR modulators, anti-inflammatory therapy may still be needed to prevent establishment and lifelong consequences of bronchiectasis. In this study, we integrated transcriptome-wide single-cell RNA sequencing data and highly multiplexed surface protein expression to create the largest comprehensive paediatric lower airway atlas of >190,000 cells from 45 bronchoalveolar lavage (BAL) samples resulting in 43 immune and epithelial cell populations, all available for exploration on CELLxGENE. We then investigated inflammatory cell responses in children with CF to show widespread gene expression dysregulation of macrophage populations in the preschool CF lung. This included alterations in pathways associated with TNF and IFN signalling, cholesterol homeostasis, as well as pulmonary fibrosis, that were further altered by the early development of bronchiectasis. We showed that the CFTR modulator ivacaftor restores some of these macrophage-related functional deficits and reduces expression of pathways associated with neutrophil infiltration, however the modulator lumacaftor/ivacaftor did not result in any detectable changes in transcriptional response. This work represents a comprehensive, multi-omic single-cell analysis of BAL from preschool children and the results may inform the future development of anti-inflammatory therapy for children with CF.
Publisher: Elsevier
Keywords: Humans; *Quinolones/therapeutic use/pharmacology; *Macrophages/immunology/drug effects; *Cystic Fibrosis/drug therapy/immunology; *Aminophenols/therapeutic use/pharmacology; Child, Preschool; Single-Cell Analysis; Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism; *Lung/immunology/pathology; *Bronchoalveolar Lavage Fluid/cytology/immunology; Female; Transcriptome; Single-Cell Gene Expression Analysis; Male; Gene Expression Profiling; Inflammation; Bal; Cftr; Children; Cystic fibrosis; Macrophages
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1016/j.mucimm.2026.03.012
Open Access at Publisher's Site: https://doi.org/10.1016/j.mucimm.2026.03.012
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-04-14 03:18:19

Last Modified: 2026-06-30 03:12:31